tyrosine kinase inhibitors and modifications of thyroid function tests

1

Tyrosine kinase inhibitors and modifications of thyroid function tests:

A review

Frédéric Illouz1,2

, Sandrine Laboureau-Soares1, Séverine Dubois

1, Vincent Rohmer

1,2,3,4,

Patrice Rodien1,2,3,4

1 CHU d'Angers, Département d'Endocrinologie Diabétologie Nutrition, Angers Cedex 09, F-

49933 France.

2 Centre de Référence des Pathologies de la Réceptivité Hormonale, CHU d'Angers, Angers

Cedex 09, F-49933 France.

3 INSERM, U694, Angers Cedex 09, F-49933 France.

4 Université d'Angers, Angers Cedex 09, F-49933 France.

Short running title: Tyrosine kinase inhibitors and thyroid function tests.

Word count: 2895 (without tables, figure and references), 42 references.

Corresponding author’s and reprint request:

F Illouz, MD

Address : CHU d'Angers, Département d'Endocrinologie, Angers Cedex 09, F-49933 France.

E-mail : [email protected]

Phone: 33(0) 2 4135 3424

Fax : 33(0) 2 4135 4700

of 21 Accepted Preprint first posted on 22 December 2008 as Manuscript EJE-08-0648

Copyright © 2008 European Society of Endocrinology.

2

Abstract

Tyrosine kinase inhibitors (TKI) belong to new molecular multitargeted therapies

which are approved for the treatment of hematologic and solid tumors. They interact with a

large variety of protein tyrosine kinases involved in oncogenesis. In 2005 the first case of

hypothyroidism was described and since then, some data has been published and has

confirmed that TKI can affect the thyroid function tests (TFT). This review analyses the

current clinical and fundamental findings about the effects of TKI on the thyroid function.

Various hypotheses have been proposed to explain the effect of TKI on the thyroid function

but those are mainly based on clinical observations. Moreover, it appears that TKI could alter

the thyroid hormone regulation by mechanisms which are specific to each molecule. The

current propositions for the management of TKI-induced hypothyroidism suggest that we

assess the TFT of the patients regularly before and during treatment by TKI. Thus, a better

approach of patients with TKI-induced hypothyroidism could improve their quality of life.

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Introduction

Protein tyrosine kinases (TK) are enzymatic proteins, usually receptors, which

catalyze the transfer of phosphate from ATP to tyrosine residues in peptides. They are

involved in the oncogenesis through various mechanisms, as described in a recent review (1):

1) a constitutively active fusion protein, created by a TK linked to a partner protein (BCR-

ABL), 2) a mutation or deletion of the kinase domain of the receptor altering its

autoregulation or the sensitivity to its ligand (Fms-like tyrosine kinase 3, stem cell factor

receptor, KIT, 3) an increased or aberrant expression of TK receptors (platelet-derived growth

factor receptor alpha, PDGFRα) or of their ligand, 4) a decrease in factors regulating TK

activity (protein tyrosine phosphatases). Excessive activation of TK is involved in survival,

proliferation, invasiveness and angiogenesis of the tumours (1).

The development of pharmacological TKI is relatively recent. These new therapies

belong to molecular targeted therapies. They block the tyrosine kinase signaling pathways that

modulate, directly or indirectly, oncogenesis (2). Even if TKI are not specific of only one TK

receptor, the majority exhibit vascular and antiangiogenic properties by interacting with

vascular endothelial growth factor (VEGF), VEGF receptors (VEGFRs) and PDGFR (2).

Other targets of TKI as RET and KIT are involved in the tumoral growth. By targeting several

TK receptors, the TKI can potentially interfere with different signaling pathways implied in

oncogenesis. Since 2005, many authors have reported changes of thyroid function tests (TFT)

among patients with different tyrosine kinase inhibitors. In this review, we analyse the effects

of four molecules: sunitinib, imatinib, motesanib and sorafenib. Indeed, only these molecules

have been associated with thyroid test abnormalities until now.

Sunitinib

Clinical data

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Sunitinib is currently approved for the treatment of advanced or metastatic renal cell

carcinoma (RCC) and gastro-intestinal stromal tumour (GIST) (3,4). Sunitinib targets the

VEGFRs, the PDGFRs, KIT and glial cell-line derived neurotrophic factor receptor (RET)

(3). All these TK receptors are involved in tumour growth, angiogenesis, metastatic potential,

which are theoretical targets of sunitinib. The administration includes repeated 6-week cycles

with 4 weeks of treatment (ON-period) followed by 2 weeks without treatment (OFF-period).

Several clinical studies have analysed the changes of TFT in patients treated with

sunitinib (table 1). In 2006, Desai et al reported the first observations of thyroid dysfunction

(5). Among 42 euthyroid subjects treated by sunitinib for GIST, 62% had an abnormal TSH

level: 36% had a persistent hypothyroidism with TSH > 7mU/l and required levothyroxine

replacement, 17% had a TSH concentration between 5 and 7mU/l, and 10% had a TSH

suppression. Since 2006, many authors have reported that sunitinib therapy is associated with

hypothyroidism in 14-85% of the patients. In the study by Mannavola et al, 46 % of patients

developed hypothyroidism requiring levothyroxine therapy and 25% had a transient elevation

of TSH (6). Rini et al showed that TFT abnormalities were consistent with hypothyroidism in

85% of the 66 subjects treated for metastatic RCC (7). Even though some patients really had

an increase in their TSH level, they preferentially had a decrease of their free tri-

iodothyronine (fT3) level rather than their free thyroxine (fT4) concentration. Wong et al

analysed the effect of sunitinib in 40 patients with different solid tumours, including mainly

GIST (8). After 5 months, sunitinib caused hypothyroidism in 53% of patients. However, the

baseline thyroid function was unknown and 18% of patients with high TSH levels had a

history of hypothyroidism. In a phase I/II trial focusing on the cardiotoxicity of sunitinib for

GIST therapy, Chu et al found 14% of hypothyroidism defined by high TSH values (9). On

average hypothyroidism appeared after 54 weeks. The latest published study prospectively

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analysed the effects of sunitinib among 59 patients with resistant RCC or with GIST (10). Its

design appears to be the best of all designs in the aforementioned studies since TFT were

performed before sunitinib was administered, as well as in the first and the last days of each

ON-period. Sixty-one percent of subjects were found to have a transient or permanent

elevated TSH, 27% of them required hormone replacement (10).

It is difficult to establish whether sunitinib-related hypothyroidism can be

symptomatic. Indeed, hypothyroidism symptoms like asthenia, anorexia or cold intolerance

are not specific, but are frequent in patients with cancer. Nevertheless, symptoms compatible

with hypothyroidism have been described for most patients with high TSH (7,10). Moreover,

levothyroxine reduced symptoms in 50% of treated patients (7,10).

The probability of hypothyroidism increases with time and with each cycle of

treatment (5,6,10). In all reported series, TSH concentration increased at the end of the ON-

phase and was near the normal range at the end of the OFF-phase, leading to intermittent

hypothyroidism. After several treatment cycles, baseline TSH levels seemed to increase,

revealing a permanent hypothyroidism. Thus, an ongoing therapy increases the risk of

developing hypothyroidism (10). Figure 1 shows the variations of TSH levels in a patient

during sunitinib therapy for metastatic renal carcinoma (Dr Damate-Fauchery, personal data).

The correction of TFT after definitive withdrawal of sunitinib is uncertain as the findings are

conflicting (5,6).

Physiopathological hypotheses

The mechanisms of alteration of TFT during sunitinib therapy are still unclear. After

the publication of Desai et al, sunitinib-induced destructive thyroiditis was advocated (5).

Indeed, in 40% of hypothyroid patients, thyroid abnormalities had a biphasic evolution with a

decrease in TSH which could correspond to a thyrotoxicosis status followed by an increase in

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TSH. Furthermore, in two subjects no thyroid gland could be identified by ultrasound.

Recently, this thyrotoxicosis period preceding hypothyroidism was reported during the first

cycles of therapy (10,11,12). Grossmann and al reported hyperthyroidism in 25% of patients

with sunitinib for renal cell carcinoma (12). In two subjects, thyrotoxicosis was severe. The

increased thyroglobulin level, the decreased iodine uptake, the progression to hypothyroidism

and the presence of lymphocytic thyroiditis on fine needle aspiration reinforced the diagnosis

of destructive thyroiditis (12). However, available data remain insufficient to assume that all

sunitinib-induced hypothyroidisms are secondary to thyroid destruction.

Some works mention the antiangiogenic effects of sunitinib. The inhibition of signal

transduction cascade of VEGF by low molecular weight inhibitors of VEGF receptor

(VEGFR) or by soluble VEGFR seems to be responsible for a capillary regression (13,14).

VEGF and VEGFRs are expressed by thyroid follicular cells and are, partly, regulated by

TSH (15-18). In mice, the inhibition of VEGFR leads to a 68% reversible reduction of thyroid

vasculature and the mouse hormonal phenotype corresponds to a primary hypothyroidism

(13). As sunitinib targets VEGFRs, it can be hypothesized that the regression of thyroid

capillary accounts for the destruction of follicular cells. Thus, by blocking VEGF signaling,

sunitinib could damage the thyroid structure and change the thyroid function.

Following the study by Desai et al, other physiopathological hypotheses have been

proposed. An iodine uptake inhibition could result in hypothyroidism (6). The majority of

patients have a significant reduction of iodine uptake during ON-period of sunitinib therapy

and this reduction is rapidly reversible during OFF-periods. Iodine uptake blocking could be

involved in sunitinib-induced hypothyroidism, as there is a negative relation between iodine

uptake and TSH concentration. Moreover, the TSH level fluctuates according to the ON or

OFF-periods. However, until now no effect of sunitinib on iodine uptake or on sodium iodide

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symporter (NIS) has been demonstrated. An in vitro study even demonstrates the contrary

(19). In FRTL-5 rat thyroid cells, sunitinib inhibited the cellular growth and increased the

iodine uptake induced by TSH or forskolin. This dose-related effect did not appear to be

mediated by NIS as there was no modification of NIS mRNA expression. The iodine efflux

was not affected either. Wong et al reported an important inhibition of peroxidase activity (8).

Sunitinib antiperoxidase potency could be 25-30% of that of propylthiouracil. This effect

could explain the latent period between the initiation of sunitinib and the development of

hypothyroidism. Thus, hypothyroidism could appear only after the release of thyroid hormone

reserve of the gland. Further research is still required because the links between peroxidase

activity and TSH have not yet been evaluated. Data regarding the sunitinib-induced alterations

of immune response is missing. Only about 4-10% of treated subjects seem to develop

thyroglobulin auto-antibodies (7,10). In contrast with interferon therapies, immunity does not

appear to participate in the thyroid dysfunction (20). Impairment of iodine organification and

reduced iodine uptake could play a role in the risk of hypothyroidism during sunitinib

treatment, but those mechanisms cannot explain the thyrotoxicosis period before

hypothyroidism. This is the reason why the hypothesis of destructive thyroiditis seems to be

the predominant effect of sunitinib-related hypothyroidism.

Imatinib

Clinical data

Imatinib is primarily approved for the treatment of Philadelphia chromosome (BCR-

ABL) positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase

and of Kit-positive GIST (21). Imatinib is a multitargeted tyrosine kinase inhibitor which

interacts with BRC-ABL, non receptor fusion tyrosine kinase, PDGFR and KIT (2).

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Imatinib-induced modifications of the thyroid function have been studied by de Groot

et al. In 2005, de Groot et al reported hypothyroidism frequency among 10 imatinib-treated

patients for medullary thyroid carcinoma (MTC) (22). Seven of them had undergone thyroid

surgery. One patient was treated for GIST. Only the seven athyreotic patients (and not the

patients with thyroid in situ) had an increased TSH concentration which approached 5 times

the upper normal value. Hypothyroidism remained subclinical as, even if fT4 and fT3 levels

were reduced by 59% and 63%, respectively, they remained within the normal range. The

same group assessed the effect of imatinib among 15 subjects with metastatic MTC (23). In

the same way, TSH changes were present only in athyreotic subjects. The fT4 and fT3 values

were not reported but there was a 210% increase of the levothyroxine replacement dose. This

effect appears rapidly after initiation of therapy and is reversible, since TSH normalized after

discontinuation of imatinib (22). Even if it seems that imatinib therapy does not alter the

thyroid function, results must be interpreted with caution, considering the low number of

subjects in those two studies.

Physiopathological hypotheses

The studies quoted above cannot clearly identify an action of imatinib on the thyroid

gland (22,23). The majority of patients treated have indeed undergone thyroidectomy and the

absence of effects of imatinib on patients with thyroid in situ does not suggest a veritable

action on thyroid tissue itself. Lately, Dora et al confirmed these results, as they showed that

imatinib did not induce any modifications of the thyroid hormonal status in 68 patients with

thyroid in situ treated for chronic myeloid leukaemia (24). Imatinib could interfere with T4

metabolism and not with thyroid hormonal synthesis. The absorption of levothyroxine did not

seem to be impaired by imatinib, since the separate administration of the two medications did

not modify TSH levels (22). The absence of changes in thyroxine-binding globulin (TBG) and

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total thyroxine levels neither supports competition for thyroid hormone-binding sites nor

supports desiodinase inhibition (22). Thus, de Groot et al suggest that imatinib could

stimulate the T4 and T3 clearances by the induction of uridine diphosphate-

glucuronosyltransferases (UGTs) (22,25). However, potential interactions between UGTs and

imatinib remain to be proven.

Motesanib (AMG 706)

Motesanib targets TK such as VEGFR, PDFGRs, KIT and RET (2). Today, motesanib

is evaluated for second line therapy in differentiated thyroid carcinoma (DTC), MTC and for

other solid tumours (sarcoma, melanoma, lung kidney, colon, GIST) (26,27,28).

The motesanib thyroid cancer study group evaluated the motesanib-induced thyroid

function modifications in a phase II safety/efficacy study (26,27). Ninety-three patients

treated for a DTC and 91 for MTC, all with levothyroxine substitution, were followed for an

average of 100 days. During therapy, almost 50% of the patients showed a TSH concentration

10 times higher of the baseline value on at least one occasion. Hypothyroidism or TSH above

the reference range was present in 22% of DTC and 61% of MCT (26,27). Thus, the

levothyroxine replacement dosages had to be increased during motesanib therapy.

No published studies deal with the interactions between motesanib and thyroid gland

function. Like imatinib, data is based on athyreotic patients. In this population, TFT changes

suggest an indirect effect of motesanib similar to that of imatinib. However, thyroid

antiangiogenic action remains possible. In mice, motesanib inhibits the proliferation of

endothelial cells and reduces vascular permeability induced by VEGF (29). In tumour

xenografts, motesanib reduces tumour growth and induces tumour regression, which is

preceded by a proapoptotic action on endothelial cells. Thus, the effects of motesanib could

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be double via action on the thyroid tissue and via action on the metabolism of thyroid

hormones. A recent study on safety and tolerance of motesanib on solid tumours did not

report the alterations of TFT and only studies in patients with thyroid in situ could highlight

the actions of motesanib on the thyroid (28).

Sorafenib (BAY 43-9006)

Sorafenib is also a multitargeted tyrosine kinase inhibitor which interacts with

VEGFRs, PDGFR-β, KIT, RET, B-RAFand C-RAF (2,30). Sorafenib is approved for the

treatment of advanced RCC and unresectable hepatocellular carcinoma (31). It has been

evaluated in lung, prostate, pancreatic, prostate cancers, melanoma, and DTC (32-34).

Abnormalities in TFT have been reported in 39 euthyroid subjects treated by sorafenib

for metastatic RCC (35). Two to four months after sorafenib initiation, 18% of subjects

presented hypothyroidism, and one quarter of them developed thyroglobulin antibodies.

Hypothyroidism would persist after sorafenib withdrawal. One patient (3%) exhibited

hyperthyroidism but its baseline thyroid status was unknown. Thyroid tests compatible with

nonthyroidal illness were described in 21% of cases.

Sorafenib inhibits VEGFR and PDGFRβ signaling pathways and reduces angiogenesis

in human tumour xenografts (30,36). In orthotopic anaplastic thyroid carcinoma xenografts,

sorafenib induces an endothelial apoptosis (37). This antiangiogenic effect results in reduced

tumour growth and improved survival of mice. Sorafenib also seems to decrease proliferation

and survival of tumour cells by blocking the RAF/MEK/ERK pathway (30,36). These

combined actions can explain the antitumoral activity of sorafenib. Nevertheless,

antiproliferative activity was not explored on non-tumoral thyroid tissue. Sorafenib could also

interact with TSH-signaling pathways. Indeed, the TSH signal transduction cascade has been

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reported to involve the RAF pathway, a target of sorafenib (38,39). However, no study has

analysed the effect of inhibition of this pathway on thyroid hormone synthesis. Such studies

could provide a better understanding of sorafenib-induced hypothyroidism.

Management of thyroid function abnormalities during TKI therapy

TKI affect thyroid function through different physiopathological mechanisms which

can impair the thyroid tissue or the thyroid hormone metabolism. Initiation of TKI therapy

requires TFT monitoring before, and during, the first weeks of therapy in all patients whether

with in situ thyroid or thyroidectomized patients. Considering available data, a monthly TSH

assessment could be performed, as we do not possess a better knowledge of the effect of each

TKI. Wolter at al proposed measuring TSH on day 1 and day 28 in the first 4 cycles of

sunitinib treatment and then every 3 cycles if the preceding TSH were normal (10). Currently,

other TKI are being evaluated (vandetanib, dasatinib..) and it would be judicious to assess

their effect on thyroid function during phase II and III trials.

The question of thyroid hormone substitution in TKI-induced hypothyroidism has

been raised recently following the publication of a report which concluded that the median

progression-free survival in sunitinib-treated patients for renal carcinoma cell was better in

patients with thyroid abnormalities (40-42). Even though levothyroxine therapy remains

debated in patients with asymptomatic or subclinical hypothyroidism, levothyroxine seems to

be necessary in TKI-induced overt hypothyroidism in order to avoid the symptoms of

hypothyroidism. Hormone replacement can be difficult during sunitinib therapy. Sunitinib

therapy is indeed proposed in cycles composed of a 4-weeks ON-period followed by a 2-

weeks OFF-period. An elevated TSH level during the OFF-period would definitely require

levothyroxine substitution, whereas an increased TSH during the ON-period could

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spontaneously return to normal in the OFF-period. Thus, a hyperthyroidism might appear if

levothyroxine substitution is introduced. That is why OFF-period TSH levels could be more

informative than ON-period TSH levels when making hormone replacement decisions.

Conclusions

TKI are new molecular targeted therapies approved for the treatment of several

haematological and solid tumours. Many studies clearly have demonstrated that TKI were

able to induce disturbances of TFT. The indications of TKI will probably be broadened and

will then increase the number of subjects with thyroid dysfunction. Oncologists and

endocrinologists must become aware of TKI-induced TFT alterations so as to detect and treat

them. Hopefully, a close collaboration between oncologists and endocrinologists should help

to improve the quality of life of these patients.

Acknowledgments

We thank Dr Claire Damatte-Fauchery for the illustration concerning the effects of

sunitinib on thyroid function. We are indebted to Pr Jacques Orgiazzi for the preparation of

this work.

Disclosure

All authors of this manuscript have no conflict of interest.

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36 Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C.

Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces

tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006 66

11851-11858.

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http://www.fda.gov/medwatch/safety/2007/Mar_PI/Nexavar_PI.pdf


19

37 Kim S, Yazici YD, Calzada G, Wang ZY, Younes MN, Jasser SA, El-Naggar AK, Myers

JN. Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma

xenografts in nude mice. Mol Cancer Ther 2007 6 1785-1792.

38 Rivas M, Santisteban P. TSH-activated signaling pathways in thyroid tumorigenesis. Mol

Cell Endocrinol 2003 213 31-45.

39 Calebiro D, de Filippis T, Lucchi S, Martinez F, Porazzi P, Trivellato R, Locati M, Beck-

Peccoz P, Persani L. Selective modulation of protein kinase A I and II reveals distinct roles in

thyroid cell gene expression and growth. Mol Endocrinol 2006 20 3196-3211.

40 Garfield D, Hercbergs A, Davis P. Unanswered questions regarding the management of

sunitinib-induced hypothyroidism. Nat Clin Pract Oncol 2007 12 674-675.

41 Garfield DH, Wolter P, Schöffski P, Hercbergs A, Davis P. Documentation of Thyroid

Function in Clinical Studies With Sunitinib: Why Does It Matter? J Clin Oncol 2008 26

5131-5132.

42 P. Wolter, C. Stefan, B. Decallonne, H. Dumez, S. Fieuws, H. Wildiers, P. Clement, D.

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Table 1 Frequency of Hypothyroidism during tyrosine kinase inhibitors therapies (sunitinb,

imatinib, motesanib and sorafenib). GIST, gastro-intestina stromal tumor; RCC, renal cell

carcinoma; MTC, medullary thyroid carcinoma; DTC, differentiated thyroid carcinoma.

Drugs Subjects (n) Indications Hypothyroidism (%)

Desai, 2006 (5) Sunitinib 42 GIST 36

Mannavola, 2007 (6) Sunitinib 24 GIST 71

Rini, 2007 (7) Sunitinib 66 RCC 85

Wong, 2007 (8) Sunitinib 40 Solid (in majority GIST) 53

Chu, 2007 (9) Sunitinib 36 GIST 14

Wolter, 2008 (10) Sunitinib 59 RCC, GIST 61

De Groot, 2005 (22) Imatinib 11 MTC, GIST 100 in athyreotic subjects

De Groot, 2007 (23) Imatinib 15 MTC 100 in athyreotic subjects

Sherman, 2008 (27) Motesanib 93 DTC 22

Tamaskar, 2007 (35) Sorafenib 39 RCC 18

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Figure 1 Serum TSH fluctuating concentrations during sunitinib therapy in a patient with

advanced renal cell carcinoma. Gray areas indicate the ON-period (with drug administration)

and white areas the OFF-period (without drug administration). Striped area corresponds to the

TSH normal range (0.35-4.5 mUI/L). With the permission of Dr Damatte-Fauchery, personal

data.

Initiation of

levothyroxine

Resumption of

levothyroxine

Withdrawal of

levothyroxine

TS

H (

mU

/l)

Times (weeks)

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tyrosine kinase inhibitors and modifications of thyroid function tests

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